The cell envelope constitutes a thick layer of highly insoluble protein on the inside of the plasma membrane of cornified epidermal cells and of other stratified squamous epithelial cells. Of several putative protein components, none has hitherto proven to be a major component because of major differences in amino acid composition, levels of mRNA or of expressed protein. We have recently identified a new protein, termed loricrin, that fulfills all of the requirements of a major constituent of the cell envelope. Loricrin clones were first identified in a mouse epidermis, and now in more detail, from human epidermis. Loricrins are glycine-rich proteins that contain the highly flexible glycine loop motif. They are crosslinked in cell envelopes by isodipeptide N(epsilon)-(gamma-glutamyl)lysine bonds. The possible role of loricrins in keratinizing disorders of epidermis is being investigated by transgenics, PCR, RFLP and genodermatoses analyses.